Multiple cell types in the nervous system express different types of opioid receptors, and there is growing evidence that interaction between different receptor subtypes modulates their function in highly significant ways. However, the mechanisms of interaction between co-expressed opioid receptor subtypes, and the pathways by which receptor interaction change receptor function remain poorly understood. We have found that interaction between mu and delta receptors may change the functional response of a cell to mu receptor-specific agonists from an inhibitory to an excitatory effect. The general goals of this proposal are to determine the cellular mechanisms of mu/delta opioid receptor interaction, including the possible formation of mu/delta heterodimers, and to determine how mu/delta receptor interaction modulates the functional responses to opioids agonists and antagonists. The specific aims of the proposal are to investigate the following hypotheses: 1) Interaction between mu and delta opioid within individual cells results in receptors with different G-protein coupling and functional responses to opioid receptor agonists and antagonists. 2) Interaction between mu and delta receptors modulates opioid receptor constitutive activity. 3) Interaction between mu and delta receptors modulates the functional response to chronic exposure to different opioids. These studies will provide new insight into the mechanisms and functions of interactions between opiold receptors, and as well as between opioid receptors and other G-protein coupled receptors. An increased understanding of these interactions may lead directly to new therapeutic approaches to pain and to the prevention and management of opioid tolerance and addiction.